EP 480717 discloses a process for the synthesis of montelukast and its pharmaceutically acceptable salts especially sodium salt. The process for the preparation comprises of reacting [(E)]-2-(2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(methanesulfonyloxy)propyl)phenyl)-2-propoxy) tetrahydropyran with methyl 1-(acetyl thiomethyl)cyclopropane acetate in presence of hydrazine, cesium carbonate in acetonitrile as a solvent to get methyl ester of montelukast in pyran protected form. The protected compound is further reacted with pyridinium p-toluene sulfonate, sodium hydroxide in a mixture of methanol and tetrahydrofuran as a solvent to afford montelukast sodium.
The drawback of this process is that, it involves more number of steps, which includes series of protection and de-protection of diol intermediate, usage of hazardous and costly raw materials such as hydrazine, pyridinium p-toluenesulonate in typical reaction conditions i.e., at very low temperatures. Hence is not suitable for commercial scale-up.
U.S. Pat. No. 5,614,632 disclose a process for the preparation of 1-(mercapto methyl)cyclopropane acetic acid, which is a key intermediate for the preparation of montelukast sodium. The said patent claimed an improved process for the preparation of montelukast sodium including the process for the preparation of its key intermediates. The drawback of this process is that, it involves the usage of pyrophoric and costly raw material such as n-butyl lithium in typical reaction conditions i.e., at very low temperatures. The processes also involves tedious workup to isolate the required product and thus results in the excess time cycle, which in turn renders the process more costly and less eco friendly thus the process is not suitable for commercial scale-up.
The styrene impurity and sulfoxide impurity (Impurity-E) of montelukast sodium were first disclosed in J. Org. Chem. 61, 8518-8525, 1996. This journal also disclosed the pathways for the formation of styrene and sulfoxide impurity.
As per the disclosed process styrene impurity was formed due to the dehydration of tertiary alcohol of montelukast when the reaction was performed in acidic media and the sulfoxide impurity is formed due to aerial oxidation of montelukast.
The purity of montelukast sodium obtained as per the prior art process is not satisfactory and for this reason a series of purification steps are required to provide a product which meets the quality requirement of pharmaceutical active ingredients.
Generally any synthetic compounds or for example montelukast sodium can contain extraneous compounds or impurities that can be derived from many sources. It is known from the art that impurities in an any API may arise from degradation of API itself, which is related to the stability of the API during storage, and the manufacturing process, including the chemical synthesis. Process impurities include unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products.
Montelukast sodium prepared as per the prior art process has five major impurities along with the unreacted starting material. The impurities which are present in montelukast sodium are designated as Impurities A, B, C, D and E. The corresponding derivatives or origin of the impurities A, B, C and D are designated as A*, B*, C* and D* respectively, which are present in the starting material compound of formula-2. The structural formulas of impurities A, B, C and D and their corresponding derivatives A*, B*, C*, D* as well as the impurity E are represented as below.

Apart from the above mentioned impurities, the dimer impurities such as diacid impurity as well as its corresponding salts have been observed in montelukast sodium. The dimer impurities are derived from the mercaptomethyl cyclopropane acetic acid intermediate compound of formula-7. The dimer impurities such as diacid and diester having the following structural formula.

Impurities in montelukast sodium or any active pharmaceutical ingredient are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing that active pharmaceutical ingredient. So it is important to reduce the impurities to meet the quality requirement of pharmaceutical active ingredients.
In order to reduce the above mentioned impurities in the montelukast sodium, the prior art methods teaches three ways of purification, those are purification of montelukast sodium or purification of montelukast organic amine salts followed by conversion of amine salts into sodium salt or by the purification of montelukast free acid. All the prior art methods involves repeated purifications at final or pre final stage without mentioning the origin/cause of the impurities. Generally repeated purifications at the final stage of any compound will lead to loss of material which increases the cost of production.
The aim of the present invention is to provide an improved process for the preparation of pure montelukast sodium through highly pure intermediate compounds free from corresponding derivatives of impurities A, B, C & D, as well as free from diacid and diester impurities.
We the present inventors found that the origin of impurities A, B, C and D which were observed in the montelukast sodium was due to the carryover of corresponding derivatives present in the starting material (i.e., compound of formula-2) and the impurity-E was observed due to an aerial oxidation of montelukast. The present invention eliminates the corresponding derivatives of so called impurities (i.e., A, B, C, D, diacid and diester impurities) present in the starting materials, by purification of the starting material (i.e., at the point of origin of impurities) which will avoids the loss of material caused by the purification in the final step as disclosed in prior art. The usage of starting materials which are free from corresponding derivatives of above said impurities leads to the highly pure montelukast sodium.
Further more the main drawback of the prior art processes is that, the removal of dicylcohexyl amine salt from the montelukast or its pharmaceutically acceptable salts requires number of purifications, which makes the process tedious. Dicyclohexylamine traces still contaminates with the montelukast or its pharmaceutically acceptable salts even after repeated purifications, thereby limiting the scope for achieving high purity and industrial applicability.
So it was the aim of the present inventors to develop a novel organic amine salts of montelukast which possessing high advantageous physico-chemical properties, high degree of crystallinity and thermodynamic stability and easily removed from the reaction mixture or from the final product by simple washing or by simple purification methods which gives the montelukast or its pharmaceutically acceptable salts free from organic amine salt traces.
In general alkali salts of any API possesses hygroscopic nature, for example montelukast sodium is highly hygroscopic in nature so it cannot be dried in a tray drier in normal atmospheric conditions as it liquefies by exposing to the atmosphere. Hence it is required to dry the material in a tray drier under specific controlled environment to control the hygroscopic nature of montelukast sodium. There is a need in the art to develop a tray drying techniques which avoids the above problems.
The patent publication US 2006/194838 discloses the needle shaped morphology of montelukast sodium which is difficult to formulate. The present inventors provide a process for the preparation of montelukast sodium in non-needle shaped morphology which is easy to formulate.
Another aspect of the present invention is to provide an improved process for the preparation of highly pure intermediate compound of formula-2.
Another aspect of the present invention is to provide a process for purification of mercaptomethyl cyclopropane acetic acid compound of formula-7.
The improved process for the preparation highly pure montelukast sodium provided by the present invention is cost effective as well as the obtained montelukast sodium is highly pure and suitable for pharmaceutical compositions.